(Applicant's Abstract) The prevalence of asthma is on the rise in developed countries, but the causes are still not well understood. Recent epidemiologic studies by our group and others suggest that high microbial burden in early life may be a protective factor for the development of atopy-related asthma during the school years. Studies performed in rural communities in Europe and Canada showed that individuals living on farms, and especially in animal farms, are less likely to develop atopy related asthma than those living in rural areas away from farms. It has also been shown that children raised on farms are exposed to higher levels of endotoxins than those raised in the same rural areas but away from farms. Experimental data suggest that exposure to endotoxin at crucial times during the development of the immune system may enhance maturation of immune responses and by this mechanism, prevent sensitization to aeroallergens. We propose to explore the complex gene by environment interactions that may underlie the potential effect of endotoxin exposure in decreasing early allergic sensitization and consequently, asthma risk. A population sample of children raised in rural areas of Europe and in whom indoor endotoxin exposure has been assessed will be studied, together with a large sample of children living in Tucson and who have been followed from birth. Both populations will be genotyped for polymorphisms in the CD14 gene and in the IL-10 gene. Other genes involved in the cellular response mechanism for endotoxin will be screened for polymorphisms. The promoter regions of the germline transcripts for IgG4 and IgE will also be screened. The main objective of these studies is to determine the mechanisms by which these genetic polymorphisms may regulate the effect of endotoxin exposure in modifying asthma risk. Specifically, we expect that the effect of endotoxin exposure on immune responses will depend on the timing and intensity of the exposure, and also on genetic variants in the receptor mechanism for endotoxin. Our studies may offer important clues as to the gene by environment interactions that control the maturation of the immune system in early life and that may predispose for the development of asthma later in life.